The molecular characterization and treatment of Chronic Lymphocytic Leukemia (CLL) has evolved significantly in the recent years. CLL was once recognized as a single disease, but is now divided into several molecularly distinct subsets. Some of these molecular subtypes [un-mutated immunoglobulin VH (IVH) gene and del(llq22-23)] are associated with poor prognosis, including a shorter period between diagnosis and the requirement of therapy and a decreased overall survival, yet their impacts on treatment outcomes are currently unknown. Other molecular markers such as del(17p13.1), overexpression of Mcl-1 protein, and mutations of p53 have been associated with resistance to conventional chemotherapy in small retrospective studies. Concurrent with these advances in molecular sub-typing, the CALGB has taken a major leadership role in advancing therapeutics in CLL, significantly raising the complete response (CR) rate (20 percent versus 4 percent) with fludarabine as compared to chlorambucil therapy on CALGB 9011. Another CALGB trial (CALGB 9712) also doubled the CR rate (to 47 percent) by administering rituximab concurrently with fludarabine. With a planned series of trials in the next calendar year, we now wish to integrate these new treatment approaches with the newly recognized CLL-specific molecular markers and genome wide profiling (eDNA or RLGS, as described in Project 3). Pursuit of this approach is supported by recommendations of the National Cancer Institute CLL State of the Science Meeting where it was recommended that all future large CLL studies have integrated within them molecular tests that facilitate possible risk stratification strategies. We have chosen to examine several recently identified molecular markers that are well substantiated but for which no large retrospective or prospective trials have been published concerning their impact on response rate, progression free survival (PFS), and overall survival (OS). We will take this a step further by utilizing genome-wide scanning to differentiate the clinical outcomes of patients with favorable molecular markers who paradoxically have an unfavorable response to treatment and short overall survival from those patients who respond favorably. Pursuit of these studies is based upon the goal of developing risk-stratified therapy for CLL within the CALGB as is currently done for AML, where treatment is assigned based upon pre-treatment molecular or genome profile features.